A(1)-ADENOSINE RECEPTOR ANTAGONISTS

Potent and selective A(1)-adenosine receptor (AR) antagonists (derivat ives of xanthine or other heterocyclic structures) have been developed during the past ten years. Recently, the problem of low water solubil ity found with these groups of compounds has been addressed with the i ntroduction of hydrophilic groups in positions tolerated by the recept or. Cloning of the Al-AR of several species, including humans, has all owed mutagenesis studies to identify the binding site for agonists and antagonists. Computer modelling of the pharmacophore has been useful for developing more potent and selective ligands. Modelling of the rec eptor protein was attempted, but remains speculative. The first genera tion of A(1)-selective AR antagonists is under clinical development fo r different indications, including dementias, such as Alzheimer's dise ase, hypertension and renal failure. New potential indications are bei ng discovered and investigated, particularly in heart (treatment of ca rdiac arrhythmias, oedemas, as positive inotropes and as cardiac prote ctants), kidney (treatment of oedemas, nephritis, nephrosis syndrome), lung (asthma, oedema, lung protective) and central nervous system (CN S) (depression, stress, coma) diseases. A(1)-selectivity is important for specific actions and for reducing undesired side-effects, e.g., in crease in locomotor activity.